Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population.

Sigrid Næss,Espen Melum,Erik Thorsby,Andre Franke,Johannes R Hov,Jochen Hampe,Stefan Schreiber,Peter J P Croucher,Marita Olsson,Annika Bergquist,Tom H Karlsen,Erik Schrumpf,Kirsten Muri Boberg,Benedicte A Lie,James A Traherne

doi:10.1371/journal.pone.0114486

Abstract

BackgroundGenetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel.Methodology/Principal FindingsA total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10−11).Conclusions/SignificanceOur study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.

Highlights

Primary sclerosing cholangitis (PSC) is a rare liver disease resulting in chronic inflammation and concentric fibrosis of the intra- and extra hepatic bile ducts
We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the major histocompatibility complex (MHC) (n518,644; genotyped and imputed) alongside previously suggested primary sclerosing cholangitis (PSC) risk determinants in the MHC, i.e. amino acid variation of DRb, a MICA microsatellite polymorphism and HLA-C and HLA-B according to PLOS ONE | DOI:10.1371/journal.pone
Unconditional multivariate regressions result in independent HLA class I and II associations In the first strategy, we started by assessing whether the HLA associations in PSC could be restricted to alleles at only one of the six classical HLA-loci genotyped (i.e. HLA-A, HLA-B, HLA-C, DRB3, DRB1 and DQB1)

Summary

Introduction

Primary sclerosing cholangitis (PSC) is a rare (prevalence 1/10,000) liver disease resulting in chronic inflammation and concentric fibrosis of the intra- and extra hepatic bile ducts. The statistically most significant genetic associations are located within the major histocompatibility complex (MHC) on chromosome 6p21. This genetic complex spans almost 4 million base pairs (Mbp), harboring approximately 260 genes. A strong genetic association within the MHC, as observed in PSC, is a hallmark of most autoimmune and immune-mediated diseases. Due to the complexity of the region, including extensive linkage disequilibrium (LD), population heterogeneity and the high density of immune-related genes, it has for most diseases been difficult to pinpoint the causal genetic variant(s) and the functional implications of the genetic associations. Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n518,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRb, a MICA microsatellite polymorphism and HLA-C and HLA-B according to PLOS ONE | DOI:10.1371/journal.pone.0114486 December 18, 2014

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